The invention relates to a new process for producing useful intermediates for the manufacture of NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a γ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, backbone.
Endogenous atrial natriuretic peptides (ANP), also called atrial natriuretic factors (ANF) have diuretic, natriuretic and vasorelaxant functions in mammals. The natural ANF peptides are metabolically inactivated, in particular by a degrading enzyme which has been recognized to correspond to the enzyme neutral endopeptidase (NEP, EC 3.4.24.11), also responsible for e.g. the metabolic inactivation of enkephalins.
Biaryl substituted phosphonic acid derivatives are known which are useful as neutral endopeptidase (NEP) inhibitors, e.g. as inhibitors of the ANF-degrading enzyme in mammals, so as to prolong and potentiate the diuretic, natriuretic and vasodilator properties of ANF in mammals by inhibiting the degradation thereof to less active metabolites. NEP inhibitors are thus particularly useful for the treatment of conditions and disorders responsive to the inhibition of neutral endopeptidase (EC 3.4.24.11), particularly cardiovascular disorders such as hypertension, renal insufficiency including edema and salt retention, pulmonary edema and congestive heart failure.
Further neutral endopeptidase (NEP) inhibitors and their synthesis are described in U.S. Pat. No. 4,722,810, U.S. Pat. No. 5,223,516, U.S. Pat. No. 4,610,816, U.S. Pat. No. 4,929,641, South African Patent Application 84/0670, UK 69578, U.S. Pat. No. 5,217,996, EP 0306879, EP 0449523, GB 02218983, WO 92/14706, JP 06234754, EP 0361365, WO 90/09374, JP 07157459, WO 94/15908, U.S. Pat. No. 5,273,990, U.S. Pat. No. 5,294,632, U.S. Pat. No. 5,250,522, EP 0636621, WO 93/09101, EP 0511940, WO 93/10773, and U.S. Pat. No. 5,217,996. Said neutral endopeptidase (NEP) inhibitors are typically prepared by using N-acyl derivatives of biphenyl alanine as key intermediates, preferably enantiomerically pure N-acyl derivatives of biphenyl alanine such as (S)-2-acylamino-3-biphenyl propanoic acid.
For example, U.S. Pat. No. 5,217,996 describes biaryl substituted 4-amino-butyric acid amide derivatives which are useful as neutral endopeptidase (NEP) inhibitors, e.g. as inhibitors of the ANF-degrading enzyme in mammals. U.S. Pat. No. 5,217,996 discloses the preparation of N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester. In the preparation of said compound N-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester is hydrogenated in the presence of palladium on charcoal.
WO 2009/090251 relates to a reaction route for preparing compound N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester, or salt thereof, wherein an alternative hydrogenation step provides improved diastereoselectivity compared to that obtained in U.S. Pat. No. 5,217,996.
Typically, synthetic methods to prepare the above mentioned biphenyl alanine derivatives in enantiomerically pure form use expensive starting materials such as non-natural D-tyrosine. Moreover, said methods require the use of trifluoromethanesulfonic anhydride, which is also expensive, to activate the phenolic hydroxyl in order to carry out the aryl coupling reaction leading to the desired biphenyl structure. One example of such a synthetic approach is described in the J. Med. Chem. 1995, 38, 1689-1700. The following Scheme 1 illustrates one of these methods:

Another method for preparing 2-acetylamino-3-biphenyl propanoic acid is reported in Chemical and Pharmaceutical Bulletin 1976, 24, 3149-3157. Said method comprises the steps i) and ii) outlined below:

A drawback of this process is that the acetyl group is removed under the reaction conditions of the first step and thus a further chemical step is necessary in order to reintroduce it. Such an undesired acetyl removal makes thus the process unattractive. Moreover, this process does not provide means to obtain enantiomerically pure 2-acylamino-3-biphenyl propanoic acid without 10 additional resolution of the racemate, e.g. by salt formation with a chiral amine, or by enzymatic resolution.
WO 2010/081410 describes a method for obtaining an enantiomerically pure chiral compound of formula (I)
wherein said method comprises reacting a compound of formula (III)
with a chiral amine of formula (V)
and resolving the resulting disasteromeric mixture of a compound of formula (II)
via crystallization.
However, one main disadvantage of any chiral resolution of racemates compared to a direct asymmetric synthesis of one of the enantiomers is that the yield cannot reach more than 50% at maximum. Though epimerization of the undesired enantiomer and resubmission to resolution is possible in some cases, it generally requires additional processing steps, and thereby creating an additional burden.
An alternative method for preparing an N-acylbiphenyl alanine is described in WO 2011/035569 and depicted in Scheme 3 below.

However, the synthetic process as summarized in Scheme 3 includes a catalytic hydrogenation step. The drawback to hydrogenation is that the catalyst required is almost always a precious metal such as palladium or platinum. In non-stereoselective hydrogenation reactions the metal is embedded as fine particles in activated carbon (1-5% metal loading is a common range). This material is then used for the hydrogenation reaction. Because many organic compounds may adhere to activated carbon, often times the catalyst cannot be reused for hydrogenation without extensive recycling, isolation and treatment of the precious metal. In addition, the desired product is obtained as racemic mixture under these conditions, with the associated disadvantages of non-stereoselective syntheses described above. In order to achieve stereoselective hydrogenations whilst using chiral metal catalysts, it is necessary to use an asymmetric ligand to induce selectivity. However, commonly used asymmetric ligands are often only accessible by complex synthetic routes and/or are very costly, therefore contributing significantly to the overall reaction costs. As a result, both non-stereoselective and stereoselective hydrogenation reactions on large scales are disadvantageous from an economic perspective.
Accordingly, there is a need for the development of an alternative synthesis of N-acyl derivatives of biphenyl alanine and related intermediates useful in the preparation for biaryl substituted 4-amino-butyric acid amide derivatives which act as NEP inhibitors, preferably of enantiomerically pure N-acyl derivatives of biphenyl alanine and related intermediates, which synthesis can be used on a commercial scale and which avoids the above-mentioned drawbacks of the prior art processes. Thus the object of the present invention is to provide a new process for preparing N-acyl derivatives of biphenyl alanine and related intermediates such as 3-biphenyl-2-aminopropan-1-ol and N-acyl derivatives thereof useful in the preparation of NEP inhibitors, preferably enantiomerically pure N-acyl derivatives of biphenyl alanine and related intermediates, which is suitable on a commercial scale.